Field of the Invention
The present invention relates to preparation and characterization of the co-crystal products formed by metoprolol and dabigatran bases with L-theanine.
Background of the Invention
The ongoing interest in modification of drug substances whose physical properties are less than desirable has led to significant study of issues associated with polymorphism and solvatomorphism. More recently, it has been recognized that many substances may cocrystallize in a single continuous lattice structure, leading pharmaceutical scientists into new areas of crystal engineering. Cocrystals are mixed crystals where the cocrystal is a structurally homogeneous crystalline material that has been formed from discrete neutral molecular species that are solids at ambient temperatures.
Cocrystals represent novel forms of drug substances that would be suitable for incorporation in pharmaceutical solid dosage forms, and should enable formulation scientists to overcome a variety of problems that are encountered during development of traditional formulations. One could consider cocrystals as being an alternative to polymorphs, solvatomorphs, and salts, as cocrystals represent a different approach to solve problems related to dissolution, crystallinity, hygroscopicity, etc.
Unfortunately, it is not yet possible to predict whether two substances will cocrystallize or not, and therefore cocrystal screening studies are largely empirical in nature.
Thrombin is a serine protease which enables the conversion of fibrinogen into fibrin during the coagulation cascade resulting in clot formation. Dabigatran, being a direct inhibitor of thrombin, blocks clot formation.
Epinephrine (Adrenalin) an arrhythmogenic catecholamine, is a powerful cardiac stimulant acting directly on the B1 receptors of the myocardium, nodal tissue, and conducting system of the heart resulting in an increased heart rate.
Metoprolol (Lopressor) whose mechanism of action as a selective B1 receptor antagonist (class II antiarrhythmic beta adrenergic blocker) acts directly on the B1 receptors of the myocardium, nodal tissue, and conducting system of the heart antagonizing the cardiac action of catecholamine like epinephrine, thereby slowing the heart rate. Metoprolol prevents epinephrine from binding to the B1 receptors by competing for the binding site.
Metoprolol is an FDA approved medication indicated in the treatment of the following arrhythmias in stable patients: ventricular tachycardia, atrial fibrillation with rapid ventricular response, atrial flutter, paroxysmal supraventricular tachycardia (except in patients with Wolff-Parkinson-White Syndrome), multifocal atrial tachycardia (except in patients with COPD).
The underlying cause of any arrhythmia needs to be determined and treated. Some causes of arrhythmias that need to be ruled out include: hypomagnesemia, hypokalemia, hyperthyroidism, digoxin toxicity, theophylline toxicity, illicit drug use (e.g., cocaine, phencyclidine, MDMA (3,4-methylenedioxymethamphetamine) “molly” or “ecstasy”); aerosol propellant inhalation, glue inhalation, lithium toxicity, tricyclic antidepressant toxicity, monoamine oxidase inhibitor toxicity, serotonin syndrome, drug-induced (pentamidine, albuterol, and vasopressors like dopamine, epinephrine, norepinephrine), pulmonary embolism, myocardial infarction, cardiomyopathy, hypoxia, licorice root tea (glycyrrhizin glabra root) when consumed regularly and in excessive amounts, and genetic etiologies. The aforementioned list of etiologies of arrhythmias is non-limiting.
Metoprolol is used in the prevention of stress-induced arrhythmias associated with inherited long QT syndrome 1 and long QT syndrome 2 (See “Long QT Syndrome.” N.p., n.d. Web. wikipedia.org/wiki/Long_QT_syndrome).
Theanine which is 5-N-Ethyl glutamine, is an ethylamide of glutamine acid. In the medical literature, theanine is known to slow the heart rate due to an attenuation of sympathetic nervous system activation (See Kimura, K. “L-Theanine Reduces Psychological and Physiological Stress Responses.” N.p., n.d. Web. ncbi.nim.nih.gov/pubmed/16930802).
Glutamine is known to increase the heart rate (See “Glutamine (Oral Route) Side Effects.” N.p., n.d. Web. mayoclinic.org/drugs-supplements/glutamine-oral-route/side-effects/DRG-20064099. Drug information provided by Micromedex; “L-Glutamine Benefits.” N.p., n.d. Web. l-glutaminebenefits.com/l-glutamine-side-effects).
Cancer cells use glutathione to detoxify doxorubicin and escort the drug out of cells. Theanine is able to interfere with this process due to its structural similarity to glutamate (steric hindrance) (See Table I). Sadzuka found that theanine could block the export of doxorubicin (Adriamycin) from cancer cells by blocking the glutamate and glutathione transporter mechanisms, resulting in an elevated level of doxorubicin within cancer cells which strongly inhibits the tumor (See Sadzuka, Yasuyuki, Tomomi Sugiyama, Toshihiro Suzuki, and Takashi Sonobe. “Enhancement of the Activity of Doxorubicin by Inhibition of Glutamate Transporter.” Toxicology Letters 123.2-3 (2001): 159-67).
Coformers depicted below are highly structurally related to L-theanine:
TABLE I  Given the structural similarity of glutamine with theanine, and the fact that glutamine increases the heart rate might have led one to deduce that theanine would also increase the heart rate. In spite of this expectation, theanine does in fact slow the heart rate. Therefore, since one could not have predicted that theanine would slow the heart rate, the effects of the metoprolol-theanine cocrystal represent an unexpected result.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operation advantages and specific objects attained by its uses, reference is made to the accompanying figures and descriptive matter in which a preferred embodiment of the invention is illustrated.